In Japan, the three most common death-causing diseases are cancer (30.3%), cardiac disease (15.3%), and cerebrovascular disease (15.2%). As the population ages, the percentage of patients with such diseases increases, which greatly affects medical costs required for treatment or nursing care. In recent years, a nursing-care insurance system for cerebrovascular disease patients has been established as a national policy.
In Japan, the number of deaths from cancer was 320,315 (i.e., 253.9 per 100,000) in 2004. In Japan, in 2003, lung cancer (22.3%) was ranked first among cancer deaths in men, followed by gastric cancer (17.2%) and liver cancer (12.5%), whereas colon cancer (14.6%) was ranked first among cancer deaths in women, followed by gastric cancer (14.2%) and lung cancer (12.3%). According to a report by the National Cancer Center in Japan, regarding five-year survival rates for major types of cancer, the five-year survival rate of pancreatic cancer patients is the lowest (only a few percent), followed by that of patients with gallbladder cancer, lung and bronchial cancer, liver cancer, esophageal cancer, etc. Ohno, Nakamura, et al. have estimated that the number of new cases of male cancers will be 501,000 in 2020 (major sites of cancer: lung, prostate gland, stomach, colon, liver, etc.), whereas the number of new cases of female cancers will be 337,000 in 2020 (major sites of cancer: breast, colon, stomach, lung, uterus, rectum, liver, etc.). Thus, cancer is predicted to become a major death-causing disease in future (as is the case at present), and development of a therapy for cancer is essential.
Cancer therapy has changed with the times. Recently, in addition to hitherto performed surgery, drug therapy, and radiotherapy, endoscopic resection of cancer tissue has been carried out, and chemotherapy for outpatients has been performed more and more. However, about 40% of cancer cases are treated through surgery at present, and radiotherapy or chemotherapy is less effective for some cancers (e.g., pancreatic cancer). In some cancer cases, chemotherapy can reduce a size of cancer tissue, but encounters difficulty in completely curing the disease. In many refractory cancer cases, adverse reactions to an anticancer agent (i.e., side effects thereof) are more pronounced than the effects of the drug.
Cerebrovascular diseases are classified into a cognitive disorder, which is caused by vascular disorder, and Alzheimer's disease, which is a neurodegenerative disease. In Japan, a number of patients with dementia caused by Alzheimer's disease (AD) has increased with adoption of Europeanized and Americanized meals and aging of the population.
AD is a neurodegenerative disease which develops various intellectual dysfunctions (including memory impairment) due to degeneration or loss of cerebral cortical neurons. An AD brain is characterized by accumulation of an abnormal protein called “β-amyloid,” which is closely related to loss of neurons (Non-Patent Document 1).
β-Amyloid is accumulated in an AD brain in the pathological form of senile plaque or vascular amyloid. From the biochemical viewpoint, β-amyloid is formed of Aβ peptide including 40 to 42 amino acid residues. Aβ is produced from APP (amyloid precursor protein) through two-step cleavage and is secreted extracellularly. In the second step, a C-terminal fragment of APP is cleaved at an intramembrane site by the protease activity of the enzyme γ-secretase, and the thus-formed Aβ is released extracellularly. Cleavage of the C-terminal fragment of APP occurs at different sites; i.e., at position 40 (90%) and at position 42 (10%) (Non-Patent Document 2). Aβ42 is more highly aggregated in the form of β-amyloid and is preferentially accumulated in an AD brain from an early stage (Non-Patent Document 3).
As has been shown, presenilin (PS) protein, which is an expression product of a major pathogenic gene of familial AD, corresponds to a catalytic subunit of γ-secretase, which is a membrane-associated aspartic protease (Non-Patent Documents 4 and 5).
γ-Secretase has been shown to be involved not only in AD but also in Notch signaling (Non-Patent Document 6). As has been known, a γ-secretase inhibitor (i.e., a low-molecular-weight compound) induces apoptosis in Kaposi's sarcoma (Non-Patent Document 7) or inhibits survival of T-ALL cells (Non-Patent Document 8). However, it has been reported that a γ-secretase inhibitor may promote malignant transformation (Non-Patent Document 9). Thus, inhibition of Notch signaling does not necessarily induce cell death in all cancers, and in the future studies will be carried out to determine whether or not a γ-secretase inhibitor can be used as a therapeutic drug for cancer.
Under such circumstances, γ-secretase has been considered important as a therapeutic target for AD or cancer, but a cancer therapeutic drug based on γ-secretase has not successfully been developed for, for example, the following reason. Since γ-secretase is a complex formed of a plurality of membrane proteins and exhibits protease activity in the membrane, difficulty is encountered in reconstituting γ-secretase while maintaining protease activity, and drug screening is not properly carried out by use of γ-secretase.
As has been known, human active γ-secretase complex is a large membrane protein complex having a molecular weight of 250 to 500 kDa or more and including the following four proteins: presenilin, nicastrin (NCT), APH-1, and PEN-2. That is, nicastrin is a constituent molecule of γ-secretase. Many attempts have been made to search for γ-secretase activity inhibitors by use of low-molecular-weight compounds, but no report has been provided to show a result of an experiment by use of an anti-nicastrin antibody for development of a γ-secretase activity inhibitor or a therapy for AD and/or cancer. Although there are many AD and cancer patients, a good drug for a treatment of the diseases has not yet been provided. Development of a therapeutic drug for AD or cancer could reduce burden of nursing care as a matter of course, along with medical costs,    Non-Patent Document 1: Selkoe D J., Physiol. Rev. 2001, 81 (2): 741-766, Alzheimer's disease: genes, proteins, and therapy    Non-Patent Document 2: Suzuki N., et al. Science 264: 1336, 1994    Non-Patent Document 3: Iwatsubo Odaka A., Suzuki N., Mizusawa H., Nukina N., Ihara Y., Neuron. 1994, 13 (1): 45-53    Non-Patent Document 4: Wolfe M S. Xia. W., Ostaszewski B L., Diehl T S., Kimberly W T., Selkoe D J. (1999), Nature 398 (6727): 513-517    Non-Patent Document 5: Li Y M., Xu M., Lai M T., Huang Q., Castro J L., DiMuzio Mower J., Harrison T., Lellis C., Nadin A., Neduvelil J G., Register R B., Sardana M K., Shearman M S., Smith A L., Shi X P., Yin K C., Shafer J A., Gardell S J. (2000), Nature 2000 Jun. 8, 405 (6787): 689-94    Non-Patent Document 6: J. Biol. Chem. 2001 Aug. 10; 276 (32): 30018-30023    Non-Patent Document 7: Oncogene. 2005 Sep. 22; 24 (42): 6333-6344    Non-Patent Document 8: Mol. Cell. Biol. 2003 January; 23 (2): 655-664    Non-Patent Document 9: Br. J. Cancer. 2005 Sep. 19; 93 (6): 709-718